Abstract
L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤−0.7, p<0.001) and EPO (r≤−0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, singlestranded RNA virus, which leads to coronavirus disease 2019 (COVID-19)
In nasopharyngeal swab samples from infected and non-infected subjects, we studied whether Dopa decarboxylase (DDC), angiotensin-converting enzyme 2 (ACE2), dACE2, ISG56 and EPO mRNA levels are associated with SARS-CoV-2 infection and viral RNA amounts
Since DDC and ACE2 expression is regulated by hypoxia [14, 17,18,19,20, 22] and the hypoxia-inducible factors (HIFs)-target immune-modulatory gene EPO [21], we concurrently examined the expression profile of EPO in COVID-19 patients compared to the non-infected individuals
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, singlestranded RNA virus, which leads to coronavirus disease 2019 (COVID-19). Severe aggravation in some patients has been associated with dysregulation of the immune response and induction of an inflammatory storm [2]. In contrast to ACE2, dACE2 protein does not bind the viral spike protein and dACE2 is an interferon-stimulated gene (ISG), induced after SARS-CoV-2 infection. DACE2 shows high expression in airway epithelial cells, in contrast to the lower levels of ACE2. The ratio of expression of the dACE2 to ACE2 is highest in nose and mouth and reduces in the lower respiratory tract. A transcriptome analysis of nasopharyngeal samples showed ACE2 induction in COVID-19 patients [6], it has been hypothesized, but not experimentally addressed, that this is due to dACE2 and not ACE2 [4]
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